Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species
Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species
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DOI：
10.1074/jbc.m111.226209
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发表时间：
2011-08-26
影响因子：
4.8
通讯作者：
Larner, Andrew C.
中科院分区：
文献类型：
--
作者：
Szczepanek, Karol;Chen, Qun;Larner, Andrew C.
STAT3转录因子在心脏中的表达具有心脏保护作用，并降低活性氧的水平。最近的研究表明，线粒体中有大量的STAT3，在那里，电子传递链的复合物I和II的最大活性是必需的。然而，尚未探讨线粒体STAT3是否在应激条件下调节心功能。产生了心肌细胞特异性过表达线粒体靶向STAT3并在dna结合域（MLS-STAT3E）发生突变的转基因小鼠。我们评估了线粒体STAT3在缺血时线粒体功能保存中的作用。在缺血条件下，表达MLS-STAT3E的心脏线粒体显示出电子传递链复合物I和II基础活性的适度降低。与whearts相比，在MLS-STAT3E心脏中，复杂i依赖的呼吸速率受到保护，免受缺血性损伤。MLS-STAT3E阻止细胞色素c在缺血时释放到细胞质中。与WT线粒体相比，缺血并没有增加MLS-STAT3E线粒体中活性氧的产生，这可能是由于MLS-STAT3E介导的部分阻断了通过复合体i的电子传递。考虑到STAT3过表达的警告，这些结果表明，线粒体STAT3介导的一种新的保护机制独立于其作为核转录因子的典型活性。
Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WThearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor.